There is increasing evidence that the response of blood vessels to various agonists is increased in hypercholesterolemia or mild atherosclerosis. This evidence is based on both in vivo and in vitro studies of the rabbit and the primate vasculature. The broad objective of the proposed study is to determine the extent of this supersensitivity in terms of the range of blood vessels and range of agonists which display the sensitivity changes. The component of the hypercholesterolemic plasma which causes the change will also be identified. Finally some of the possible mechanisms for the sensitivity change will be investigated. A previously described method using a hpercholesterolemic diet will be used to induce the abnormality in rabbits. The plasma and tissue cholesterol levels will be monitored. The length-tension relationship, the responses to nerve stimulation, and the response to exogenous agonists will be tested in vitro. Those tissues which show an altered response will be further investigated to determine if the super-sensitivity can be reproduced in vitro by adding various components of the abnormal plasma to normal vessels. Finally the components of the adrenergic neuroeffector mechanism will be examined to determine which are altered. This study may indicate one possible mechanism for vasospasm leading to tissue ischemia which may be an important factor in conditions such as angina or cerebral transient ischemic attacks.